CN1338455A - Process for preparing quinolone carboxylic acid - Google Patents
Process for preparing quinolone carboxylic acid Download PDFInfo
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- CN1338455A CN1338455A CN00123446.3A CN00123446A CN1338455A CN 1338455 A CN1338455 A CN 1338455A CN 00123446 A CN00123446 A CN 00123446A CN 1338455 A CN1338455 A CN 1338455A
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- China
- Prior art keywords
- carboxylic acid
- formula
- compound
- fluoro
- chloro
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- XOQQVKDBGLYPGH-UHFFFAOYSA-N 2-oxo-1h-quinoline-3-carboxylic acid Chemical compound C1=CC=C2NC(=O)C(C(=O)O)=CC2=C1 XOQQVKDBGLYPGH-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 238000004519 manufacturing process Methods 0.000 title abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 30
- 238000002360 preparation method Methods 0.000 claims description 26
- 150000001875 compounds Chemical class 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 13
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 9
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 239000011737 fluorine Substances 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 9
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 2
- 150000004820 halides Chemical class 0.000 abstract 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- 125000003277 amino group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- -1 quinolone carboxylic acids Chemical class 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- ACXQCLCOXPDOQV-UHFFFAOYSA-N ethyl 1-fluoro-4-oxoquinoline-3-carboxylate Chemical compound C1=CC=C2C(=O)C(C(=O)OCC)=CN(F)C2=C1 ACXQCLCOXPDOQV-UHFFFAOYSA-N 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 238000001816 cooling Methods 0.000 description 12
- 238000001953 recrystallisation Methods 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 9
- 239000000376 reactant Substances 0.000 description 9
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 229960004756 ethanol Drugs 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 5
- UXTMROKLAAOEQO-UHFFFAOYSA-N chloroform;ethanol Chemical compound CCO.ClC(Cl)Cl UXTMROKLAAOEQO-UHFFFAOYSA-N 0.000 description 5
- 230000006837 decompression Effects 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- HJZQMXIVAIMIQA-UHFFFAOYSA-N 1-fluoro-4-oxoquinoline-3-carboxylic acid Chemical class C1=CC=C2C(=O)C(C(=O)O)=CN(F)C2=C1 HJZQMXIVAIMIQA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 4
- WACNXHCZHTVBJM-UHFFFAOYSA-N 1,2,3,4,5-pentafluorobenzene Chemical compound FC1=CC(F)=C(F)C(F)=C1F WACNXHCZHTVBJM-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 229960000935 dehydrated alcohol Drugs 0.000 description 3
- HHBWJFABYNBJCG-UHFFFAOYSA-N ethyl 1-cyclopropyl-5,6,7,8-tetrafluoro-4-oxoquinoline-3-carboxylate Chemical compound C12=C(F)C(F)=C(F)C(F)=C2C(=O)C(C(=O)OCC)=CN1C1CC1 HHBWJFABYNBJCG-UHFFFAOYSA-N 0.000 description 3
- CXHHBNMLPJOKQD-UHFFFAOYSA-M methyl carbonate Chemical compound COC([O-])=O CXHHBNMLPJOKQD-UHFFFAOYSA-M 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 150000007660 quinolones Chemical class 0.000 description 3
- VZGOSDDTMGRQAY-UHFFFAOYSA-N 1,2,3,4,5-pentafluorobenzene pentan-3-one Chemical compound C(C)C(=O)CC.FC=1C(=C(C(=C(C1)F)F)F)F VZGOSDDTMGRQAY-UHFFFAOYSA-N 0.000 description 2
- 230000002924 anti-infective effect Effects 0.000 description 2
- 229960005475 antiinfective agent Drugs 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000007790 solid phase Substances 0.000 description 2
- AVGWCJLTQZQLCN-UHFFFAOYSA-N 2-fluoro-3-methoxybenzoic acid Chemical class COC1=CC=CC(C(O)=O)=C1F AVGWCJLTQZQLCN-UHFFFAOYSA-N 0.000 description 1
- MEXUTNIFSHFQRG-UHFFFAOYSA-N 6,7,12,13-tetrahydro-5h-indolo[2,3-a]pyrrolo[3,4-c]carbazol-5-one Chemical compound C12=C3C=CC=C[C]3NC2=C2NC3=CC=C[CH]C3=C2C2=C1C(=O)NC2 MEXUTNIFSHFQRG-UHFFFAOYSA-N 0.000 description 1
- ROWLEBZCGSXVNM-UHFFFAOYSA-N CC(=O)OC(C(=O)C1=CC(=CC(=C1)F)OC)Cl Chemical compound CC(=O)OC(C(=O)C1=CC(=CC(=C1)F)OC)Cl ROWLEBZCGSXVNM-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
- C07C49/807—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen all halogen atoms bound to the ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Quinoline Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
A process for preparing quinolone carboxylic acid is disclosed. Its formula consists of 4 groups, of which R1 consists of H, halide molecules and amino-group; R2 consists of halide molecules; R3 consists of H, halide molecules, C1-C2 alkoxyland CN; and R4 consists of C3-C6 naphthenic base, C1-C4 alkyl, C1-C4 alkoxyl C1-C4 alkyl, C1-C4 oxyalkyl C1-C4 alkyl and H molecule.
Description
The present invention relates to the preparation method of quinolone carboxylic acid, particularly is the preparation method of feedstock production quinolone carboxylic acid with the phenyl polyhalide ethyl ketone.
The quinolones anti-infectives is because its excellent performance obtains people in recent years and pays close attention to widely.Quinolone carboxylic acid is the important intermediate of this class anti-infectives, and various quinolones are to be precursor with these intermediates invariably, and is synthetic and derive through the number step again.Therefore, synthetic these quinolone carboxylic acids are obviously extremely important in the process of preparation quinolones.
Reported the method for multiple synthetic quinolone carboxylic acid already, as from 2,4,5-three fluoro-3-methoxybenzoic acids synthesize Moses's carboxylic acid, begin synthetic department carboxylic acid fluoride from pentafluorobenzoic acid, but these methods do not reach very satisfactory effect on yield, therefore, still have the space of improvement.The present invention proposes based on this.
The object of the present invention is to provide a kind of method for preparing quinolone carboxylic acid of novelty, from the raw material phenyl polyhalide ethyl ketone synthetic quinolone carboxylic acid of starting with.Method steps of the present invention is less relatively, can reach comparatively ideal yield.
The method of preparation formula of the present invention (I) quinolone carboxylic acid,
Wherein: R
1Be H, halogen atom, amino,
R
2Be halogen atom,
R
3Be hydrogen, halogen atom, C
1-C
4Alkoxyl group, CN,
R
4Be C
3-C
6Cycloalkyl, C
1-C
4Alkyl, C
1-C
4Alkoxy C
1-C
4Alkyl,
C
1-C
4Alkylamino C
1-C
4Alkyl, hydrogen atom comprises step: i) with formula (II) compound
R wherein
1, R
2, R
3Definition the same, R
7Be halogen atom,
Obtain formula (III) compound with carbonate reaction,
Wherein, R
8Represent methylidene or ethyl;
Ii) with formula (III) compound and ortho-formiate and formula (IV) compound R
4NH
2Reaction obtains the formula V compound;
Iii) the formula V compound is obtained formula (VI) compound at alkaline condition ShiShimonoseki ring;
Iv) formula (VI) compound hydrolysis is obtained formula (I) compound.
In the method for the invention, the R in formula (I) compound
1Be preferably hydrogen, fluorine or amino; R
2Be preferably fluorine or chlorine; R
3Be preferably fluorine, CN or OCH
3R
4Be preferably cyclopropyl, cyclohexyl.
(II) available methyl carbonate of the reaction of formula compound and carbonic ether or ethyl ester carry out, and in organic solvent, alkali carries out under existing usually in this reaction.Preferably use carbonic ether itself as solvent, used alkali can be selected sodium hydride or sodium alkoxide.
The reaction of formula (III) compound and ortho-formiate is carried out in the presence of diacetyl oxide usually, direct and formula (IV) R in reaction back
4NH
2Reaction obtains the formula V compound.
The cyclisation of formula V reactant is carried out in the organic solvent under alkaline condition, and solvent preferably uses DMF, and alkali then can be selected Anhydrous potassium carbonate for use, thus the formula of obtaining (VI) compound.
Guan Huanhou gets corresponding quinolone carboxylic acid ester with this area ordinary method and is hydrolyzed to corresponding formula (I) compound carboxylic acid.
In method of the present invention, work as R
1Be NH
2The time, can be from R
1For the corresponding formula of halogen (VI) compound transforms, reaction is as showing:
Below the invention will be further described with specific embodiment.Embodiment 1 is from 2, and 4-two chloro-5-fluoro-3-methoxyacetophenones prepare Moses's carboxylic acid preparation 2,4-two chloro-5-fluoro-3-anisoyl methyl acetates
With 2,4-two chloro-5-fluoro-3-methoxyacetophenone 80.6g (0.34mol), methylcarbonate 1000ml mixes.At room temperature add content is 50%NaH 50.0g (1.04mol) in batches, finishes in 80 ℃ of reaction 3h.Reactant is carefully poured in the frozen water that contains little acetic acid, used extracted with diethyl ether, washing, anhydrous sodium sulfate drying.Steam ether, reclaim excessive methylcarbonate after, resistates is recrystallization in methyl alcohol, 2,4-two chloro-5-fluoro-3-anisoyl-methyl acetate 80.8g (0.274mol), mp 50-53 ℃, yield 80.6%.Preparation 2-(2,4-two chloro-5-fluoro-3-anisoyl)-3-cyclopropylamino acrylate acid methyl esters
With 2,4-two chloro-5-fluoro-3-anisoyl methyl acetate 73.8g (0.25mol), 66.6g triethyl orthoformate (0.45mol) and 77.4g diacetyl oxide (0.72mol) mix, and at 150 ℃ of reaction 2.5h, decompression steams the lower boiling fraction.In residue, add the 250ml anhydrous methanol; under the frozen water cooling, add cyclopropylamine 14.5g (0.25mol); finish and at room temperature react 2h; suction filtration; with sherwood oil-hexanaphthene double solvents recrystallization; get 2-(2,4-two chloro-5-fluoro-3-anisoyl)-3-cyclopropylamino acrylate acid methyl esters 66.0g (0.182mol), yield 72.9%.Preparation 1-cyclopropyl-7-chloro-6-fluoro-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid methyl esters
2-(2,4-two chloro-5-fluoro-3-anisoyl)-3-cyclopropylamino acrylate acid methyl esters 62.6g (0.173mol) is dissolved among the 220ml DMF, adds anhydrous K
2CO
334.7g (0.35mol), in 40-45 ℃ of stirring reaction 2.5h, TLC follows the tracks of.Reactant is poured in the 800ml frozen water, leach solid, water 100ml * 2 thorough washing, oven dry, refluxed 15 minutes with 95% methyl alcohol 120ml again, drying is filtered in cooling, get white solid 1-cyclopropyl-7-chloro-6-fluoro-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid methyl esters 50.8g (0.156mol), mp184-187 ℃, yield 90.1%.Preparation 1-cyclopropyl-7-chloro-6-fluoro-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid
With 1-cyclopropyl-7-chloro-6-fluoro-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid methyl esters 28.6g (0.088mol), acetate 160ml, the mixture of water 100ml and vitriol oil 18ml was 100-110 ℃ of stirring reaction 40 minutes.The reaction mass cooling is filtered.Precipitation gets product 1-cyclopropyl-7-chloro-6-fluoro-8-methoxyl group-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid (Moses's carboxylic acid) 25.2g (0.081mol), mp 195-199 ℃, yield 91.8% with chloroform-ethanol recrystallize.Embodiment 2 is from 3-cyano group-2, and 4-two chloro-5-fluoro acetophenones prepare 8-cyano group quinolone carboxylic acid and prepare 3-cyano group-2,4-two chloro-5-fluoro benzoyl ethyl acetate
With 3-cyano group-2,4-two chloro-5-fluoro acetophenone 78.9g (0.34mol), diethyl carbonate 1000ml mixes, and at room temperature add content is 50%NaH 50.0g (1.04mol) in batches, finishes in 80 ℃ of reaction 3h.Reactant is carefully poured in the frozen water that contains little acetic acid, used extracted with diethyl ether, washing, anhydrous sodium sulfate drying.Steam ether, reclaim excessive diethyl carbonate after, resistates is recrystallization in toluene, 3-cyano group-2,4-two chloro-5-fluoro benzoyl ethyl acetate 86.6g (0.285mol), yield 83.7%.Preparation 2-(3-cyano group-2,4-two chloro-5-fluoro benzoyls)-3-cyclopropylamino acrylate acetoacetic ester
With 3-cyano group-2,4-two chloro-5-fluoro benzoyl ethyl acetate 76.0g (0.25mol), 66.6g triethyl orthoformate (0.45mol) and 77.4g diacetyl oxide (0.72mol) mix, and at 150 ℃ of reaction 2.5h, decompression steams the lower boiling fraction.In residue, add the 250ml dehydrated alcohol, under the frozen water cooling, add cyclopropylamine 14.5g (0.25mol).Finish and at room temperature react 2h, suction filtration with sherwood oil-hexanaphthene double solvents recrystallization, gets 2-(3-cyano group-2,4-two chloro-5-fluoro benzoyls)-3-cyclopropylamino acrylate acetoacetic ester 65.0g (0.175mol), and mp 125-129 ℃, yield 70.1%.Preparation 8-cyano group-1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester
2-(3-cyano group-2,4-two chloro-5-fluoro benzoyls)-3-cyclopropylamino acrylate acetoacetic ester 64.2g (0.173mol) is dissolved among the 220ml DMF, adds anhydrous K
2CO
334.7g (0.35mol), in 40-45 ℃ of stirring reaction 2.5h, TLC follows the tracks of.Reactant is poured in the 800ml frozen water, leach solid, water 100ml * 2 thorough washing, oven dry, refluxed 15 minutes with 95% ethanol 120ml again, drying is filtered in cooling, get white solid 8-cyano group-1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester 53.2g (0.159mol), mp 196-199 ℃, yield 91.9%.Preparation 8-cyano group-1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid
With 8-cyano group-1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester 29.4g (0.088mol), acetate 160ml, the mixture of water 100ml and vitriol oil 18ml was 100-110 ℃ of stirring reaction 40 minutes.The reaction mass cooling is filtered, and precipitation gets product 8-cyano group-1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid 23.8g (0.0775mol), mp 288-293 ℃, yield 88.1% with chloroform-ethanol recrystallize.Embodiment 3 prepares penta fluoro benzene formyl radical ethyl acetate from penta fluoro benzene ethyl ketone preparation department carboxylic acid fluoride
With penta fluoro benzene ethyl ketone 71.4g (0.34mol), diethyl carbonate 1000ml mixes, and at room temperature add content is 50%NaH 50.0g (1.04mol) in batches, finishes in 80 ℃ of reaction 3h.Reactant is carefully poured in the frozen water that contains little acetic acid, used extracted with diethyl ether, washing, anhydrous sodium sulfate drying.Steam ether, reclaim excessive diethyl carbonate after, decompression steams the fraction 80.5g (0.286mol) of penta fluoro benzene formyl radical ethyl acetate (112-121 ℃/8 Pa), yield 84.0%.Preparation 2-(penta fluoro benzene formyl radical)-3-cyclopropylamino acrylate acetoacetic ester
With penta fluoro benzene formyl radical ethyl acetate 70.5g (0.25mol), 66.6g triethyl orthoformate (0.45mol) and 77.4g diacetyl oxide (0.72mol) mix, and at 150 ℃ of reaction 2.5h, decompression steams the lower boiling fraction.In residue, add the 250ml dehydrated alcohol and under the frozen water cooling, add cyclopropylamine 14.25g (0.25mol).Finish and at room temperature react 2h, suction filtration with sherwood oil-hexanaphthene recrystallization, gets 2-(penta fluoro benzene formyl radical)-3-cyclopropylamino acrylate acetoacetic ester 62.8g (0.18mol), and mp 88-91 ℃, yield 72.0%.Preparation 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester
With 2-(penta fluoro benzene formyl radical)-3-cyclopropylamino acrylate acetoacetic ester 60.4g (0.173mol), be dissolved among the 220ml DMF, add anhydrous K
2CO
334.7g (0.35mol), in 40-45 ℃ of stirring reaction 2.5h, TLC follows the tracks of.Reactant is poured in the 800ml frozen water, leached solid, water 100ml * 2 thorough washing, oven dry refluxed 15 minutes with 95% ethanol 120ml again, cooling, filter, drying gets white solid 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester 53.0g (0.161mol), mp 169-171 ℃, yield 93%.Preparation 5-benzamido group-1-cyclopropyl-6,7,8-three fluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester
With 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester 53.0g (0.161mol), benzylamine 15.4ml, the mixture of Anhydrous potassium carbonate 37.0g and acetonitrile 220ml are at 100-110 ℃ of stirring heating 1h, and TLC follows the tracks of, and steams solvent.Resistates is recrystallization in ethanol.Get 5-benzamido group-1-cyclopropyl-6,7,8-three fluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester 53.7g (0.129mol), mp133-135 ℃, yield 80.0%.Preparation 5-amino-1-cyclopropyl-6,7,8-three fluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester
With 5-benzamido group-1-cyclopropyl-6,7,8-three fluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester 46.2g (0.111mol) is dissolved in 200ml acetate and the ethanol mixed solvent, adds the 0.5g5%Pd/C catalyzer, at room temperature feeds H
2, TLC follows the tracks of, and reacts about 3h.Leach solid phase prod, and be dissolved in chloroform, refilter, remove catalyzer.Filtrate steams solvent, and resistates is recrystallization in chloroform-ethanol double solvents, gets 5-amino-1-cyclopropyl-6,7,8-three fluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester 32.4g (0.0944mol), mp 235-237 ℃, yield 85.0%.Preparation 5-amino-1-cyclopropyl-6,7,8-three fluoro-1.4-dihydro-4-Oxoquinoline-3-carboxylic acids
With 5-amino-1-cyclopropyl-6,7,8-three fluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester 28.7g (0.088mol), acetate 160ml, the mixture of water 100ml and vitriol oil 18ml was 100-110 ℃ of stirring reaction 40 minutes.The reaction mass cooling is filtered.Precipitation gets product 5-amino-1-cyclopropyl-6,7,8-three fluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid (department's carboxylic acid fluoride) 25.6g (0.086mol), mp 293-295 ℃, yield 98.0% with chloroform-ethanol recrystallize.Embodiment 4 is from 2,4,6-three chloro-3,5-difluoro acetophenone preparation department carboxylic acid fluoride preparation 2,4,6-three chloro-3,5-difluoro benzoyl ethyl acetate
With 2,4,6-three chloro-3,5-difluoro acetophenone 88.2g (0.34mol), diethyl carbonate 1,000ml mixes, and at room temperature add content is 50%NaH 50.0g (1.04mol) in batches, finishes in 80 ℃ of reaction 3h.Reactant is carefully poured in the frozen water that contains little acetic acid, used extracted with diethyl ether, washing, anhydrous sodium sulfate drying.Steam ether, reclaim excessive diethyl carbonate after, resistates is recrystallization in toluene, 2,4,6-three chloro-3,5-difluoro benzoyl ethyl acetate 93.3g (0.276mol), yield 81.2%.Preparation 2-(2,4,6-three chloro-3,5-difluoro benzoyl)-3-cyclopropylamino acrylate acetoacetic ester
With 2,4,6-three chloro-3,5-difluoro benzoyl ethyl acetate 82.9g (0.25mol), 66.6g triethyl orthoformate (0.45mol) and 77.4g diacetyl oxide (0.72mol) mix, and at 150 ℃ of reaction 2.5h, decompression steams the lower boiling fraction.In residue, add the 250ml dehydrated alcohol, under the frozen water cooling, add cyclopropylamine 14.5g (0.25mol).Finish and at room temperature react 2h, suction filtration with sherwood oil-hexanaphthene double solvents recrystallization, gets 2-(2,4,6-three chloro-3,5-difluoro benzoyl)-3-cyclopropylamino acrylate acetoacetic ester 74.5g (0.187mol), yield 74.6%.Preparation 1-cyclopropyl-5,7-two chloro-6,8 two fluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester
With 2-(2,4,6-three chloro-3,5-difluoro benzoyl)-3-cyclopropylamino acrylate acetoacetic ester 68.9g (0.173mol), be dissolved among the 220ml DMF, add anhydrous K
2CO
334.7g (0.35mol), in 40-45 ℃ of stirring reaction 2.5h, TLC follows the tracks of.Reactant is poured in the 800ml frozen water, leached solid, water 100ml * 2 thorough washing, oven dry refluxed 15 minutes with 95% ethanol 120ml again, and cooling is filtered.Drying gets white solid 1-cyclopropyl-5,7-two chloro-6,8 two fluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester 60.4g (0.167mol), mp 191-195 ℃, yield 96.4%.Preparation 5-benzyl amino-1-cyclopropyl-7-chloro-6,8 two fluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester
With 1-cyclopropyl-5,7-two chloro-6,8 two fluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester 58.3g (0.161mol), benzylamine 15.4ml, the mixture of Anhydrous potassium carbonate 37.0g and acetonitrile 220ml is at 100-110 ℃ of stirring heating 1h, TLC follows the tracks of, and steams solvent.Resistates is recrystallization in ethanol, gets 5-benzyl amino-1-cyclopropyl-7-chloro-6,8 two fluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester 58.3g (0.135mol), yield 83.7%.Preparation 5-amino-1-cyclopropyl-7-chloro-6,8 two fluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester
With 5-benzyl amino-1-cyclopropyl-7-chloro-6,8 two fluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester 48.0g (0.111mol) is dissolved in 220ml acetate and the ethanol mixed solvent, adds the 0.5g5%Pd/C catalyzer, at room temperature feeds H
2, TLC follows the tracks of, and reacts about 3h.Leach solid phase prod, and be dissolved in chloroform, refilter, remove catalyzer.Filtrate steams solvent, and resistates is recrystallization in chloroform-ethanol double solvents, gets 5-amino-1-cyclopropyl-7-chloro-6,8 two fluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester 32.0g (0.093mol), yield 83.9%.Preparation 5-amino-1-cyclopropyl-7-chloro-6,8 two fluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid
With 5-amino-1-cyclopropyl-7-chloro-6,8 two fluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid ethyl ester 30.1g (0.088mol), acetate 160ml, the mixture of water 100ml and vitriol oil 18ml was 100-110 ℃ of stirring reaction 40 minutes.The reaction mass cooling is filtered.Precipitation gets product 5-amino-1-cyclopropyl-7-chloro-6,8 two fluoro-1,4-dihydro-4-Oxoquinoline-3-carboxylic acid (department's carboxylic acid fluoride) 26.8g (0.0852mol), mp 283-287 ℃, yield 96.8% with chloroform-ethyl alcohol recrystallization.
Claims (5)
1. the preparation method of a formula (I) quinolone carboxylic acid,
Wherein: R
1Be H, halogen atom, amino,
R
2Be halogen atom,
R
3Be hydrogen, halogen atom, C
1-C
4Alkoxyl group, CN,
R
4Be C
3-C
6Cycloalkyl, C
1-C
4Alkyl, C
1-C
4Alkoxy C
1-C
4Alkyl
C
1-C
4Alkylamino C
1-C
4Alkyl, hydrogen atom comprises step: i) with formula (II) compound
R wherein
1, R
2, R
3Definition the same, R
7Be halogen atom,
Obtain formula (III) compound with carbonate reaction,
Wherein, R
8Represent methylidene or ethyl;
Ii) with formula (III) compound successively with ortho-formiate and formula (IV) compound R
4NH
2Reaction obtains the formula V compound;
Iii) the formula V compound is obtained formula (VI) compound at alkaline condition ShiShimonoseki ring;
Iv) formula (VI) compound hydrolysis is obtained formula (I) compound.
2. according to the process of claim 1 wherein R
1Be selected from H, fluorine, chlorine, amino, R
2Be selected from chlorine, fluorine, R
3Be selected from fluorine, chlorine, CN, C
1-C
4Alkoxyl group, R
4Be selected from C
3-C
6Cycloalkyl.
3. according to the method for claim 2, wherein
R
3Be selected from fluorine, CN, OCH
3,
R
4Be selected from C
3-C
6Cycloalkyl.
4. according to the method for claim 3, wherein
R
1Be selected from hydrogen, fluorine, amino,
R
2Be selected from fluorine,
R
4Be selected from cyclopropyl, cyclohexyl.
5. also can comprise according to the process of claim 1 wherein
In step I v) with R
1For the compound of halogen atom is converted into corresponding R
1Step for aminocompound.
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN00123446.3A CN1338455A (en) | 2000-08-16 | 2000-08-16 | Process for preparing quinolone carboxylic acid |
| PCT/CN2001/001156 WO2002059094A1 (en) | 2000-08-16 | 2001-07-06 | A new process for preparing a quinolone-carboxylic acid |
| US10/344,643 US6699992B2 (en) | 2000-08-16 | 2001-07-06 | Process for preparing quinolonecarboxylic acids |
| EP01980134A EP1319656B1 (en) | 2000-08-16 | 2001-07-06 | A new process for preparing a quinolone-carboxylic acid |
| AT01980134T ATE337304T1 (en) | 2000-08-16 | 2001-07-06 | NEW PROCESS FOR PRODUCING A QUINOLOONE CARBOXYLIC ACID |
| JP2002559396A JP2004517149A (en) | 2000-08-16 | 2001-07-06 | Method for producing quinoline carboxylic acid |
| DE60122539T DE60122539T2 (en) | 2000-08-16 | 2001-07-06 | Process for the preparation of quinolinecarboxylic acids |
| CN01814188.9A CN1219769C (en) | 2000-08-16 | 2001-07-06 | New process for preparing quinolone-carboxylic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN00123446.3A CN1338455A (en) | 2000-08-16 | 2000-08-16 | Process for preparing quinolone carboxylic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1338455A true CN1338455A (en) | 2002-03-06 |
Family
ID=4589879
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN00123446.3A Pending CN1338455A (en) | 2000-08-16 | 2000-08-16 | Process for preparing quinolone carboxylic acid |
| CN01814188.9A Expired - Fee Related CN1219769C (en) | 2000-08-16 | 2001-07-06 | New process for preparing quinolone-carboxylic acid |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN01814188.9A Expired - Fee Related CN1219769C (en) | 2000-08-16 | 2001-07-06 | New process for preparing quinolone-carboxylic acid |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US6699992B2 (en) |
| EP (1) | EP1319656B1 (en) |
| JP (1) | JP2004517149A (en) |
| CN (2) | CN1338455A (en) |
| AT (1) | ATE337304T1 (en) |
| DE (1) | DE60122539T2 (en) |
| WO (1) | WO2002059094A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102260172A (en) * | 2011-03-30 | 2011-11-30 | 山东先达化工有限公司 | Method for preparing 2-chloro-5-alkylcarbonyl acetyl-4-fluorophenoxyacetyl compound |
| CN107987074A (en) * | 2017-10-27 | 2018-05-04 | 浙江美诺华药物化学有限公司 | A kind of synthetic method of Pradofloxacin |
| CN114933543A (en) * | 2022-07-21 | 2022-08-23 | 山东国邦药业有限公司 | Synthetic method of 3-cyclopropylamino-2- (2, 4-dichloro-5-fluorobenzoyl) methyl acrylate |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100519158B1 (en) * | 2002-12-21 | 2005-10-06 | 주식회사유한양행 | A process for preparation of quinolone carboxylate derivatives |
| US8187483B2 (en) * | 2006-08-11 | 2012-05-29 | Jason Plumhoff | Method to minimize CD etch bias |
| US8063066B2 (en) | 2007-03-19 | 2011-11-22 | Takeda Pharmaceutical Company Limited | MAPK/ERK kinase inhibitors |
| US20090043646A1 (en) * | 2007-08-06 | 2009-02-12 | International Business Machines Corporation | System and Method for the Automated Capture and Clustering of User Activities |
| CN103450068B (en) * | 2012-05-27 | 2015-09-16 | 重庆常捷医药化工有限公司 | A kind of synthetic method of Ziprasidone intermediate |
| AU2019260015C1 (en) * | 2018-04-25 | 2024-11-21 | Elanco Animal Health Gmbh | Process for the hydrolysis of quinolone carboxylic esters |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4730000A (en) * | 1984-04-09 | 1988-03-08 | Abbott Laboratories | Quinoline antibacterial compounds |
| NZ225926A (en) * | 1987-09-08 | 1990-04-26 | Sterling Drug Inc | 7-pyridinyl-4-oxo-3-quinolinecarboxylic acid derivatives, and pharmaceutical compositions |
| US5075319A (en) * | 1987-09-08 | 1991-12-24 | Sterling Drug Inc. | Pyridinyl-quinolone compounds, their preparation and use |
| ES2049640B1 (en) * | 1992-06-18 | 1994-12-16 | Genesis Para La Investigacion | PROCEDURE FOR THE PREPARATION OF QUINOLIN CARBOXYLIC ACIDS. |
| KR100242355B1 (en) * | 1994-08-02 | 2000-03-02 | 데이비드 엠 모이어 | Method for producing antimicrobial compound |
| JP2000119221A (en) * | 1998-10-14 | 2000-04-25 | Kyorin Pharmaceut Co Ltd | Method for producing (2,4,5-trifluoro-3-methoxybenzoyl) acetic acid ester derivative and intermediate for producing the same |
-
2000
- 2000-08-16 CN CN00123446.3A patent/CN1338455A/en active Pending
-
2001
- 2001-07-06 AT AT01980134T patent/ATE337304T1/en not_active IP Right Cessation
- 2001-07-06 JP JP2002559396A patent/JP2004517149A/en active Pending
- 2001-07-06 CN CN01814188.9A patent/CN1219769C/en not_active Expired - Fee Related
- 2001-07-06 WO PCT/CN2001/001156 patent/WO2002059094A1/en not_active Ceased
- 2001-07-06 EP EP01980134A patent/EP1319656B1/en not_active Expired - Lifetime
- 2001-07-06 DE DE60122539T patent/DE60122539T2/en not_active Expired - Lifetime
- 2001-07-06 US US10/344,643 patent/US6699992B2/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102260172A (en) * | 2011-03-30 | 2011-11-30 | 山东先达化工有限公司 | Method for preparing 2-chloro-5-alkylcarbonyl acetyl-4-fluorophenoxyacetyl compound |
| CN102260172B (en) * | 2011-03-30 | 2013-11-06 | 山东先达农化股份有限公司 | Method for preparing 2-chloro-5-alkylcarbonyl acetyl-4-fluorophenoxyacetyl compound |
| CN107987074A (en) * | 2017-10-27 | 2018-05-04 | 浙江美诺华药物化学有限公司 | A kind of synthetic method of Pradofloxacin |
| CN107987074B (en) * | 2017-10-27 | 2020-12-29 | 浙江美诺华药物化学有限公司 | Synthetic method of prafloxacin |
| CN114933543A (en) * | 2022-07-21 | 2022-08-23 | 山东国邦药业有限公司 | Synthetic method of 3-cyclopropylamino-2- (2, 4-dichloro-5-fluorobenzoyl) methyl acrylate |
| CN114933543B (en) * | 2022-07-21 | 2022-10-28 | 山东国邦药业有限公司 | Synthetic method of 3-cyclopropylamino-2- (2,4-dichloro-5-fluorobenzoyl) methyl acrylate |
Also Published As
| Publication number | Publication date |
|---|---|
| US6699992B2 (en) | 2004-03-02 |
| EP1319656B1 (en) | 2006-08-23 |
| CN1219769C (en) | 2005-09-21 |
| DE60122539T2 (en) | 2007-05-03 |
| DE60122539D1 (en) | 2006-10-05 |
| EP1319656A4 (en) | 2004-09-29 |
| CN1447797A (en) | 2003-10-08 |
| ATE337304T1 (en) | 2006-09-15 |
| JP2004517149A (en) | 2004-06-10 |
| US20030166936A1 (en) | 2003-09-04 |
| WO2002059094A1 (en) | 2002-08-01 |
| EP1319656A1 (en) | 2003-06-18 |
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